1. Prevention of UTI in children with VU reflux: management controversies Moshe Efrat MD September 2006

2. Vesicoureteral Reflux (VUR)  Retrograde passage of urine from bladder to upper urinary tract  VUR = most common urologic abnormality in kids  1% newborns  30 - 45% of children with UTI  UTI (upper) = most common serious bacterial infection of children in the developed world in the age of conjugate pneumococcal and H. flu vaccines (Israel is not there yet!! – why?)

3. Two clinical presentations VUR  Prenatal:  male > female, VUR diagnosed prenatally (by US)  Severe VUR common  Significant rates spontaneous resolution, but  Renal hypoplasia and dysplasia frequent  Increased risk renal failure and hypertension  Postnatal:  Mostly female  Presents as febrile UTI  Spontaneous resolution is a function  of age and grade  and if 1 or 2 sided

4. VUR - grading  GRADING — The International Reflux Study Group standardized grading the severity of VUR based on findings from a contrast voiding cystourethogram (VCUG).  Grade I — Reflux only fills the ureter without dilation.  Grade II — Reflux fills the ureter and the collecting system without dilation.  Grade III — Reflux fills and mildly dilates the ureter and the collecting system with mild blunting of the calyces.  Grade IV — Reflux fills and grossly dilates the ureter and the collecting system. One-half of the calyces are blunted.  Grade V — Massive reflux grossly dilates the collecting system. All the calyces are blunted with a loss of papillary impression and intrarenal reflux may be present. There is significant ureteral dilation and tortuosity.

7. Principles of management  Premise: VUR can cause upper UTI by bringing bacteria to the kidneys  Results: renal scarring, loss of parenchyma  reflux nephropathy:  Potential for hypertension, decreased renal function, proteinuria, renal failure/ end stage renal disease  Management: based on -  Identification of kids with VUR  Prevention of renal damage due to reflux

8. How to prevent damage due to VUR?  Medical vs surgical approach  Not clear which is more effective!  Medical:  VUR resolves spontaneously by age 4 -5 years  Continuous antibiotics  sterile urine  VUR with sterile urine is assumed benign  Most appropriate antibiotics: TMP-SMX, nitrofurantoin  Not β-lactams!?!? Why? …  Increased bacterial resistance

9. More concerns about medical therapy  Long-term antibiotics may  complications:  minor to severe - including bone marrow suppression, Stevens-Johnson syndrome  Adherence (compliance)  Breakthrough infection  Need to monitor reflux with either VCUG or radionuclide cystography (RNC), both with discomfort and radiation

10. The main controversy  Does antibiotic prophylaxis of kids with VUR really prevent recurrent upper UTI and concomitant renal scarring?  Over the last 5-6 years this has been increasingly questioned / debated and to a certain extent studied …

12. Antibiotic prophylaxis (ABP) - studies  Background: ABP recommended for all grades VUR  Most studies to date: compare [ABP with surgery] to ABP alone, or compare ABP with surgery  Meta-analysis ( Wheeler, et al, Arch Dis Child 2003; 88:688-594 ): 1 randomized, controlled study found no difference in UTI risk with ABP, either continual or intermittent, vs no ABP  No large, randomized, prospective trials comparing ABP+ with ABP- in VUR!!!

16. Aims  Evaluate the role of VUR in affecting frequency and severity of UTI and renal scarring after APN  Determine whether ABP reduces frequency and/or severity of UTI and/or prevents renal parenchymal damage in patients with mild-moderate VUR (grades I, II, III only)

17. The study  Randomized, controlled study  N= 236 children, 3 months – 18 years  APN = acute pyelonephritis: pyuria, fever, positive culture (>10 5 ) + DMSA confirmation  All tested for VUR by VCUG  2 groups:  113 VUR grades I-III and 115 no VUR  After initial treatment for APN, both groups randomized: +/- antibiotic prophylaxis (ABP)

19. Conclusion: antibiotics do not prevent APN nor renal scarring in patients with mild or no VUR!!! Results:  Overall UTI recurrence 20.1%  - ABP: recurrence 22.4% VUR, 23.3% no VUR (NS)  +ABP: recurrence 23.6% VUR, 8.8% no VUR (NS, but close, p=0.63)  Most recurrences at 9-12 months, most cystitis (DMSA nl), APN only 5.5%  No clear-cut advantage for +ABP  All recurrences were with resistant bacteria!  More APN in +VUR than in -VUR (8 vs 4, but NS)

20. Results, continued  6/8 recurrent APN were in VUR grade III  2/8 in grade II, none in grade I  4 recurrences in non-VUR (2 ABP+, 2 ABP-)  Cystitis also VUR III, II >>VUR I Renal scars:  Only 5.9% developed scars (1 year F/U only!)  7 VUR+, 6 VUR- (NS)  Similar scarring rates ABP+ and ABP- (NS)  Increased scarring with increase grade VUR (NS)  No difference in scarring in VUR vs non-VUR

21. Conclusions at 1 year endpoint: 1. Antibiotics do not prevent cystitis, APN or renal scarring in patients with mild to moderate or no VUR!!! 2. ABP  UTIs with resistant bacteria 3. ABP in VUR+  more APN than in VUR- (NS)

22. The Editorial:

23. Fact or fantasy I  The study is highly problematic:  1 year follow-up only  1 year follow-up required, no ITT analysis in those not completing 1 year  Low incidence APN  Low rate renal scarring  Non-standardized ABP:  either trimethoprim-sulfamethoxazole (TMP-SMX) or nitrofurantoin  no placebo given to controls

24. Fact or fantasy II  Therefore, too few patients, too short a time period, and maybe the wrong population (VUR I-III), maybe wrong antibiotics - to reach conclusions of significance …  Current study: trend for more UTI and more scarring with increasing grades of VUR …  III > II > I  Important: no evaluation of severe VUR (grades IV, V)  Therefore results are not applicable to these patients !

25. Discussion  UTI pathogenesis related to bacterial binding to uroepithelial receptors   No reason to think that VUR increases UTI incidence, but …  Reasonable to think that VUR increases APN (vs lower UTI) incidence in those with propensity for UTI = trend but not significant in some studies  Scarring is a function of APN and not sterile reflux: good evidence exists

26. ABP should prevent recurrent UTI – few good data to support this!  2 potential barriers to successful ABP for UTI:  Adherence (compliance) difficult over years, also antibiotic adverse effects, though rare, increase with exposure time  Maybe recurrences mostly at 9-12 months indicate decline in adherence?  Emergence of antimicrobial resistance

27. Which drugs are used?  Nitrofurantoin or TMP-SMX  Theory: absorption high in the in GI tract - colon flora not “exposed” = protected from antibiotics  little induction of resistance  Problem – are areas where TMP-SMX cannot be used: high % GI flora resistant (Israel?)  Other agents (e.g. β-lactams) are theoretically poor choices  Colonic bacteria exposed to low AB levels  Within weeks  GI colonized primarily with bacteria inherently or newly resistant

28. Another issue  Is there any proof that prevention of UTI by continuous ABP prevents scarring better than very early initiation of therapy for APN?  No studies performed

29. Possible solutions?  Use rotating ABP schedule parallel to ABP for chronic lung disease, switching drug q2-4 weeks  Few data for UTI, some potentially encouraging  Use non-antibiotic prophylaxis e.g. methenamine mandelate  When urine pH <6, methenamine  formic acid (like formaldehyde)  Problem: urine acidification required

30. Suggestions?  Additional studies required:  To clarify ABP use in VUR grades I,II, III   Larger, better designed, longer F/U, ITT …  To study VUR grades III, IV, V  Until new data:  For all (?) VUR (severe > moderate > mild), continue using ABP (or surgery for high grade, non-resolving VUR)  If TMP-SMX inappropriate epidemiologically, maybe nitrofurantoin should be used > others

31. What about previous studies?  Not a lot of data  Good systematic review of data available up to 2005 …

36. Our questions: antibiotics, yes or no, which, and when?  Medical vs surgical therapy?  Not clear!  Meta – analysis ( Wheeler, et al, Arch Dis Child 2003; 88:688-594 (: found 7 randomized, controlled studies, ABP vs surgery, n = 859  4 studies: no difference after 5 years  2 studies: less febrile UTI, at 5 years, surgery (10%) vs ABP (22%)  But no difference in scarring!

37. Meta-analysis, continued  4 studies: no differences in scarring after 5 years  5% overall risk of new scars by DMSA  4 studies: no differences in renal growth  2 studies: no difference in hypertension or end-stage renal disease  Lack of information about surgical vs medical adverse events!!

38. Conclusions  9 reimplantations required to prevent 1 febrile UTI!  No reduction in rate of renal scarring!  Hardly seems wise to prefer surgical therapy  Except?...

40. Rationale AUA guidelines  Low grade VUR, VUR in very young kids  good chance spontaneous resolution so prefer ABP  The older kids get or the higher grade the VUR, ABP still recommended but surgery is an option especially if bilateral disease or renal scarring exists  Only in children ≥6 years old with grade V VUR is surgery preferred since the likelihood of spontaneous resolution is very low

41. If ABP follow-up …  Close monitoring to identify breakthrough  Urine-analysis and cultures whenever UTI possible  Surveillance cultures q 3-4 months  RNC > VCUG monitoring of VUR ~ yearly

43. So, in conclusion …  Until new data:  For all (?) VUR (severe > moderate > mild) …  continue using ABP  or surgery for high grade, non- resolving VUR  Nitrofurantoin preferred!?

44. Thanks!  Questions?  Comments?  Protests?